6-110622894-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015076.5(CDK19):c.952A>G(p.Met318Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CDK19 NM_015076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

CDK19 (HGNC:19338): (cyclin dependent kinase 19) This gene encodes a protein that is one of the components of the Mediator co-activator complex. The Mediator complex is a multi-protein complex required for transcriptional activation by DNA binding transcription factors of genes transcribed by RNA polymerase II. The protein encoded by this gene is similar to cyclin-dependent kinase 8 which can also be a component of the Mediator complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42184627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK19	NM_015076.5	c.952A>G	p.Met318Val	missense_variant	10/13	ENST00000368911.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK19	ENST00000368911.8	c.952A>G	p.Met318Val	missense_variant	10/13	1	NM_015076.5	P1
CDK19	ENST00000323817.7	c.772A>G	p.Met258Val	missense_variant	11/14	1
CDK19	ENST00000413605.6	c.640A>G	p.Met214Val	missense_variant	9/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460156 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726478

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 28, 2021

ACMG classification criteria: PM2, PP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;.
Eigen	Benign	0.047
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
REVEL	Benign	0.27
Sift4G	Benign	0.21	T;T;T
Polyphen		0.42	.;B;.
Vest4		0.65
MutPred		0.71		.;Loss of ubiquitination at K322 (P = 0.0907);.;
MVP		0.51
MPC		1.7
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1778804193; hg19: chr6-110944097;